The present invention provides compositions that specifically bind to HER2 and methods for the use of such compositions for the treatment of cancer.
The HER family of receptor tyrosine kinases are important mediators of cell growth, differentiation and survival. The receptor family includes four distinct members including epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2 or p185neu), HER3 (ErbB3) and HER4 (ErbB4 or tyro2).
HER2 was originally identified as the product of the transforming gene from neuroblastomas of chemically treated rats. Amplification of the human homolog has observed in breast and ovarian cancers and correlates with a poor prognosis. Overexpression of HER2 (frequently but not uniformly due to gene amplification) has also been observed in other carcinomas including carcinomas of the stomach, endometrium, salivary gland, lung, kidney, colon, thyroid, pancreas and bladder. HER2 can also be overexpressed in prostate cancer.
The HER receptors are generally found in various combinations in cells and heterodimerization is thought to increase the diversity of cellular responses to a variety of HER ligands (Earp et al. Breast Cancer Research and Treatment 35: 115-132 (1995)). While EGF and TGFα do not bind HER2, EGF stimulates EGFR and HER2 to form a heterodimer, which activates EGFR and results in transphosphorylation of HER2 in the heterodimer. Dimerization and/or transphosphorylation appear to activate the HER2 tyrosine kinase. See Earp et al., supra. Likewise, when HER3 is co-expressed with HER2, an active signaling complex is formed and antibodies directed against HER2 are capable of disrupting this complex (Sliwkowski et al., J. Biol. Chem., 269:14661-14665 (1994)).
Numerous antibodies targeting HER2 have been described in the art (see, e.g., Hudziak et al., Mol. Cell. Biol. 9:1165-1172 (1989); U.S. Pat. No. 5,677,171; Fendly et al. Cancer Research 50:1550-1558 (1990); Kotts et al. In vitro 26(3):59A (1990); Sarup et al. Growth Regulation 1:72-82 (1991); Shepard et al. J. Clin. Immunol. 11: 117-127 (1991); Kumar et al. Mol. Cell. Biol. 1:979-986 (1991); Lewis et al. Cancer Immunol. Immunother. 37:255-263 (1993); Pietras et al. Oncogene 9:1829-1838 (1994); Vitetta et al. Cancer Research 54:5301-5309 (1994); Sliwkowski et al. J. Biol. Chem. 269(20):14661-14665 (1994); Scott et al. J. Biol. Chem. 266:14300-5 (1991); D'souza et al. Proc. Natl. Acad. Sci. 91:7202-7206 (1994); Lewis et al. Cancer Research 56:1457-1465 (1996); and Schaefer et al. Oncogene 15:1385-1394 (1997).
Other HER2 antibodies with various properties have been described in Tagliabue et al. Int. J. Cancer 47:933-937 (1991); McKenzie et al. Oncogene 4:543-548 (1989); Maier et al. Cancer Res. 51:5361-5369 (1991); Bacus et al. Molecular Carcinogenesis 3:350-362 (1990); Stancovski et al. PNAS (USA) 88:8691-8695 (1991); Bacus et al. Cancer Research 52:2580-2589 (1992); Xu et al. Int. J. Cancer 53:401-408 (1993); WO94/00136; Kasprzyk et al. Cancer Research 52:2771-2776 (1992); Hancock et al. Cancer Res. 51:4575-4580 (1991); Shawver et al. Cancer Res. 54:1367-1373 (1994); Arteaga et al. Cancer Res. 54:3758-3765 (1994); Harwerth et al. J. Biol. Chem. 267:15160-15167 (1992); U.S. Pat. No. 5,783,186; and Klapper et al. Oncogene 14:2099-2109 (1997).
Trastuzumab (HERCEPTIN®; see U.S. Pat. No. 5,821,337), a recombinant humanized version of the murine HER2 antibody 4D5, is clinically active in patients with HER2-overexpressing metastatic breast cancers that have received extensive prior anti-cancer therapy (Baselga et al., J. Clin. Oncol. 14:737-744 (1996)). To target the HER signaling pathway, Pertuzumab (PERJETA™; see Patent Publication WO2001/00245) was developed as a humanized version of the murine antibody 2C4 that inhibits the dimerization of HER2 with other HER receptors, thereby inhibiting ligand-driven phosphorylation and activation, and downstream activation of the RAS and AKT pathways. Ado-trastuzumab emtansine (T-DM1; KADCYLA®) is an antibody drug conjugate of trastuzumab linked to the cytotoxic agent mertansine approved for use in patients with HER2-overexpressing metastatic breast cancers resistant to trastuzumab.
Although, the therapeutic efficacy of trastuzumab in breast carcinoma is well demonstrated, it is strictly limited and only approved for 30% of breast cancer patients whose tumor overexpress HER2. 70% of the breast cancer patients do not or insufficiently respond to trastuzumab because their individual tumor do not overexpress or do not sufficiently express HER2. In other cancers and/or individual cancers, HER2 is overexpressed in a significant percentage of cases ranging from 43 to 69%, However, as a rule, the levels of HER2 expression are in principle low in the majority of tumors. Furthermore, the-overexpression of HER2 receptors is often caused by encoding gene amplification (Hynes et al., Nat Rev Cancer 5:341 (2005)). Thus, the present day consensus is that anti-HER2 monoclonal antibody therapy is inefficient in tumors with low HER2 expression or missing overexpression. Furthermore, resistance to these anti-HER2 antibodies is a significant problem.
Given the lack of an effective anti-HER2 therapy in specific cancers expressing low levels of HER2 and resistance to the current therapies, there is a need for improved antibodies capable of effectively binding to cancer cells expressing a wider range of levels of HER2 and inhibiting their growth via, for example, (i) Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and/or (ii) cytotoxic action due to payloads conjugated to the antibodies as Antibody Drug Conjugates (ADC) and/or (iii) inhibiting receptor mediating signaling (e.g. by inhibiting receptor dimerization and/or mediating receptor internalization).
Thus, it is an object of the present disclosure to provide improved immunotherapeutic agents that effectively inhibit HER2-mediated cell signaling that can be used for the treatment of HER2-expressing cancers, including cancers where HER2 is not expressed at high levels.